Synthesis and Medicinal Impacts of Novel 3,3′-Bihalocoumarins and Their Precursors, 7-Halocoumarin-3-acetic Acids

Abstract

Objective: Despite significant advances in drug discovery, effective treatments for diseases such as cancer, bacterial infections, diabetes, and chronic inflammatory conditions remain an urgent challenge for humanity. Methods: In this study, four novel 3,3′-bihalocoumarins (denoted as (BH1–BH4)) were synthesized via the coupling of their corresponding precursors, 7-halocoumarin-3-acetic acids (B1–B4), with various 4-halosalicylaldehydes. The molecular structures of the synthesized compounds were confirmed using spectroscopic techniques, including IR, ¹H, and ¹³C NMR. The bioactive potential of the precursors and their derivatives was assessed based on six selected pharmacological properties. The dual inhibitory effect on 5-LOX and COX enzymes was evaluated against three interrelated targets, while antioxidant activity was assessed using two radical scavenging assays. The cytotoxic effects were examined using four cancer cell lines, while cytocompatibility was evaluated on a normal cell line. The antidiabetic potential was tested against two relevant enzymatic targets, and antibacterial activity was assessed against four pathogenic bacterial strains. Results and Discussion: The findings suggest that these synthesized compounds hold promise as bioactive agents. They demonstrated varying degrees of antioxidant activity, no significant toxicity toward normal or cancerous cells, minimal influence on glucose metabolism, and limited antibacterial activity. Notably, precursor (B1) exhibited potent COX-1 inhibitory activity, making it a promising scaffold for developing selective COX-1 inhibitors. The 3,3′-bihalocoumarins, particularly (BH1), showed strong selective COX-2 inhibition, suggesting their potential as lead compounds for COX-2-targeted drug development. Furthermore, precursor (B1) selectively inhibited Salmonella typhi proliferation, highlighting its potential as an antibacterial agent against this pathogen. In silico pharmacokinetic analysis indicated that these compounds have favorable oral bioavailability. Conclusions: The synthesized compounds present a promising basis for the development of biosafe and pharmacologically active scaffolds for novel therapeutics.